Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice.

Abstract

Spinal muscular atrophy is a progressive motor neuron disease caused by a deficiency of survival motor neuron. In this study, we evaluated the efficacy of intravenous administration of a recombinant adeno-associated virus (AAV1) vector encoding human insulin-like growth factor-1 (IGF-1) in a severe mouse model of spinal muscular atrophy. Measurable quantities of human IGF-1 transcripts and protein were detected in the liver (up to 3 months postinjection) and in the serum indicating that IGF-1 was secreted from the liver into systemic circulation. Spinal muscular atrophy mice administered AAV1-IGF-1 on postnatal day 1 exhibited a lower extent of motor neuron degeneration, cardiac and muscle atrophy as well as a greater extent of innervation at the neuromuscular junctions compared to untreated controls at day 8 posttreatment. Importantly, treatment with AAV1-IGF-1 prolonged the animals' lifespan, increased their body weights and improved their motor coordination. Quantitative polymerase chain reaction and western blot analyses showed that AAV1-mediated expression of IGF-1 led to an increase in survival motor neuron transcript and protein levels in the spinal cord, brain, muscles, and heart. These data indicate that systemically delivered AAV1-IGF-1 can correct several of the biochemical and behavioral deficits in spinal muscular atrophy mice through increasing tissue levels of survival motor neuron.

• Authors: Li-Kai Tsai, Chien-Lin Chen, Chen-Hung Ting, Sue Lin-Chao, Wuh-Liang Hwu, James C Dodge, Marco A Passini, Seng H Cheng
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 22 Issue 8 Pg. 1450-1459 (Aug 2014) ISSN: 1525-0024 [Electronic] United States
• PMID: 24814151 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• IGF1 protein, human
• Smn1 protein, mouse
• Survival of Motor Neuron 1 Protein
• Insulin-Like Growth Factor I

Topics

• Animals
• Dependovirus (genetics)
• Disease Models, Animal
• Genetic Therapy (methods)
• Genetic Vectors (administration & dosage)
• Humans
• Injections, Intravenous
• Insulin-Like Growth Factor I (administration & dosage, genetics)
• Liver (metabolism)
• Mice
• Muscular Atrophy, Spinal (blood, genetics, physiopathology, therapy)
• Survival of Motor Neuron 1 Protein (genetics, metabolism)
• Treatment Outcome